Prostaglandin System Research Articles

Indomethacin blocks the anorexic action of interleukin-1

It has been reported recently that the central nervous system actions of interleukin-1 are mediated by the prostaglandin system in the brain. The present study was therefore performed in order to examine the hypothesis that indomethacin, an inhibitor of prostaglandin biosynthesis, might alleviate the interleukin-1-induced suppression of food intake in rats. The i.p. injection of interleukin-1 (2 μg/rat) resulted in a significant decrease in food intake. The pre-injection of indomethacin (0.5 mg/rat), however, completely blocked the anorexic action of the monokine, while indomethacin on its own did not affect food intake. These results suggested that indomethacin might be clinically useful for improvement of the anorexic state of patients with acute infectious diseases.

Prostaglandin l2 and glucocorticoid-induced rise in arterial pressure in the rat

The mechanism of glucocorticoid-induced hypertension is not known. Although glucocorticoids can exert an inhibitory effect on prostaglandin synthesis in vitro, their in vivo influence on this system is controversial. The goal of the present study was to determine whether dexamethasone-induced hypertension in Wistar rats is due to inhibition of the synthesis of the vasodilator prostaglandin I2 (PGI2) in vivo. Dexamethasone caused a profound reduction (7 +/- 1 versus 21 +/- 5 ng per 24 h) in the urinary excretion of PGI-M (PGI-M), a major metabolite of PGI2, and a sustained rise in systolic arterial pressure which was maximal after 5 days (144 +/- 9 versus 103 +/- 3 mmHg). A study of the metabolism of [3H]-labeled 6-oxo-PGF1 alpha and PGI2 revealed that dexamethasone exerted a dual action on the prostaglandin system in vivo: an inhibition of PGI2 biosynthesis and an alteration of its metabolism, both effects contributing to the observed reduction in urinary levels of PGI-M. Exogenous arachidonic acid induced a fourfold increase in urinary PGI-M in normal rats (from 14 +/- 3 to 61 +/- 6 ng per 24 h). Despite a large decrease upon addition of dexamethasone, urinary PGI-M remained in the high-normal range in arachidonic acid-treated rats (21 +/- 8 ng per 24 h). Arachidonic acid exerted antihypertensive effects which were marginal initially but significant in the later phase of dexamethasone-induced hypertension (124 +/- 8 versus 139 +/- 8 mmHg in arachidonic acid-treated versus control rats after 7 days of dexamethasone).(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Properties of Linoleic Acid and Fish Oil Omega-3 Fatty Acids Independent of the Prostaglandin System

Polyunsaturated fatty acids of the omega-6 and the omega-3 series have been shown to lower arterial pressure in humans and in various models of experimental hypertension by uncharacterized mechanisms. The objectives of our study were to compare the antihypertensive properties of linoleic acid (omega-6 series) and of fish oil fatty acids (omega-3 series) in a model of hypertension induced by the continuous subcutaneous infusion of angiotensin II in the rat and to determine whether or not their antihypertensive effects were mediated by the biosynthesis of vasodilator prostaglandins of classes 2 or 3. Linoleic acid and fish oil fatty acids (administered by subcutaneous injections) were equally potent in reducing, by half, the rise in systolic arterial pressure induced by the chronic infusion of angiotensin II. These antihypertensive effects were observed in the absence of any significant influence of either linoleic acid or fish oil fatty acids on the systemic and the renal synthesis of PGI2 or on the renal formation of PGE2 in vivo. Indomethacin caused a profound inhibition of the biosynthesis of PGI2 but not of PGE2 and could only partially neutralize the antihypertensive effects of linoleic acid and of fish oil fatty acids. These results suggest that, in this model of angiotensin II-induced hypertension, linoleic acid and fish oil fatty acids exert equipotent antihypertensive effects which are mainly independent of the prostaglandin system.

Modulating influence of dietary lipid intake on the prostaglandin system in adult men.

We evaluated the effect of moderate dietary changes on the prostaglandin system by measuring the urinary excretion of 7 alpha-hydroxy-5,11-dioxo-tetranorprostane-1,16-dioic acid (PGE-M). In a crossover design, twenty-four free-living male subjects in good health (24 to 54 years of age) were fed two diets: (i) Regular (R) diet, 41% energy (en%) from fat, P/S 0.59, M/S 0.96; (ii) Experimental (E) diet, 19 en% from fat, P/S 1.31, M/S 1.48. Diet R contained 13.9 g/day of neutral detergent fiber (NDF) and about 600 mg/day of cholesterol per 3200 kcal; Diet E contained 35.5 g/day NDF and about 280 mg/day cholesterol. Each controlled-diet period lasted ten weeks. The menu cycle was 7 days, and all diets were calculated to provide adequate amounts of essential nutrients. The PGE-M excretion rates were determined in 24-hr urine by stable-isotope dilution gas chromatography-mass spectrometry in the selected ion-monitoring mode. Low-fat Diet E, with an intake of 6.6 en% from polyunsaturates, was associated with an average 14.2% reduction in PGE-M daily output, compared to high-fat Diet R with a 9.3 en% from polyunsaturates (P = 0.046). These results support the view that dietary lipid changes can significantly alter the in vivo production of E-series prostaglandins. We cannot conclude, however, if this apparent diet effect was brought about by the change in linoleate intake alone or was the result of complex biochemical interactions among individual fatty acids, both saturated and unsaturated.

Acute cardiovascular and renal effects of human calcitonin gene-related peptide.

Acute cardiovascular and renal effects of 25 micrograms IV human calcitonin gene-related peptide (hCGRP) have been studied in four normotensive and untreated subjects, in the absence and the presence of indomethacin, a prostaglandin synthesis-blocking agent. Intravenous infusion of hCGRP, alone, caused a transient but significant increase in heart rate (HR), hypotension, and facial flushing. Along with these effects, a positive inotropic action of hCGRP was documented by a noninvasive poligraphy. Furthermore, a significant increase in the catecholamines (norepinephrine and epinephrine), in the cyclic nucleotide (cyclic AMP and cyclic GMP) plasma levels, and a small decrease in total calcium with no change in inorganic phosphorus serum levels, occurred. Also acute renal hCGRP induced effects were observed, as a significant increase in urinary volume and in the urinary calcium, sodium, potassium, and chloride excretion. Indomethacin did not affect all the cardiovascular, metabolic, and renal hCGRP-induced effects. These results are in agreement with the hypothesis that hCGRP acts on the heart, vessels, and kidney, directly or indirectly, by the mediation of other vasodilating agents or systems excluding the prostaglandin system.

The Influence of Various Degrees of Cardiac Failure, Chronic Medical Treatment, and Acute Additional Enoximone Application on the Parameters of the Vasopressor System

The characteristics of norepinephrine and epinephrine as well as plasma renin activity, angiotensin II, aldosterone. vasopressin. and atrial natriuretic factor (ANF) were examined in 64 patients (mean age of 52 ± 16 years) with dilated cardiomyopathy. The findings were grouped according to the NYHA classification and compared with a normal cohort of 38 patients (mean age of 42 ± 10 years). Furthermore, the influence of different cardioactive substances used in the treatment of cardiac failure was analyzed in more detail. Patients in NYHA class II already demonstrated an increased activity of the sympathicoadrenal, renin-angiotensin-aldosterone system (RAAS), vasopressin, and ANF system. The highest values were found in patients of NYHA class IV. In these patients, norepinephrine was enhanced by a factor of 7, epinephrine by a factor of 2, plasma renin activity by a factor of 7, angiotensin II by a factor of 2.5, aldosterone by a factor of 5, vasopressin by a factor of 1.5, and ANF by a factor of 4 compared with those in normal subjects. The highest correlation coefficient was found for norepinephrine (r = 0.84). The acute application of 1–2 mg/kg of body weight of enoximone in patients with dilated cardiomyopathy (n = 15) resulted only in a significant lowering of the atrial natriuretic factor as an indicator for drug-induced unloading effects (venous pooling). All the parameters showed only a tendency; in none could statistical significance be established. Application of 0.75 mg/kg of body weight of enoximone i.v. in patients with coronary artery disease (n = 17) has no direct influence either on the sympathoadrenal, the ANF, or the prostaglandin systems. It could be demonstrated that the mode of medical treatment influences the parameters of vasoconstrictor systems in different ways

MECHANISMS OF ENHANCED PRESSOR RESPONSES IN EARLY STAGE OF ONE-KIDNEY, ONE CLIP HYPERTENSION IN RATS

Pressor responses to vasoconstrictors are increased in both clinical and experimental hypertension. Previous studies from our laboratory showed exaggerated pressor responses to vasoconstrictors in prehypertensive rabbits of renal hypertension. Although these results have revealed important roles of several humoral factors such as renin-angiotensin system and prostaglandin systems, many other humoral factors and neurological mechanisms may be involved in enhanced pressor responses. Furthermore, humoral factors could modulate vascular reactivity via neurogenic system, e.g. baroreflex. The present study examined 1) a role of angiotensin II in enhanced pressor responses in early stage of one-kidney, one clip renal hypertension in rats (2 days after renal artery stenosis : 2-day clipped rats), using [1-Sar, 8-Ile] angiotensin II, specific antagonist of angiotensin II ; 2) a role of serotonin, one of the other humoral factors, in the enhanced pressor responses in this model, using ketanserin, a specific antagonist of 5-HT2 ; and 3) changes in baroreflex sensitivity to determine whether baroreflex causally relates to this pressor hyperresponsiveness. Mean arterial pressure was slightly higher in the 2-day clipped rats than in sham-operated rats. Pressor responses to norepinephrine, arginin vasopressin and serotonin were exaggerated in the 2-day clipped rats than in the sham-operated rats. This hyperresponsiveness was attenuated by administering [1 -Sar, 8 -Ile] angiotensin II and ketanserin either of which did not alter mean arterial pressure. Baroreflex sensitivity was studied by measuring changes in arterial pressure and pulse interval in responses to bolus injections of phenylephrine. Baroref ex sensitivity was not decreased but markedly increased in the 2-day clipped rats and was unaffected by the infusion of [1-Sar, 8-Il] angiotensin II. These results provide evidence that 1) in the 2-day clipped rats there are exaggerated pressor responses to norepinephrine, arginin vasopressin and serotonin ; 2) angiotensin II and serotonin play significant roles in these increased pressor responses ; and 3) the changes in baroreflex sensitivity do not participate in the pressor hyperresponsiveness in the 2-day clipped rats, because the increased sensitivity should have attenuated this response, not exaggerated it.

The Influence of Various Degrees of Cardiac Failure, Chronic Medical Treatment, and Acute Additional Enoximone Application on the Parameters of the Vasopressor System

The characteristics of norepinephrine and epinephrine as well as plasma renin activity, angiotensin II, aldosterone, vasopressin, and atrial natriuretic factor (ANF) were examined in 64 patients (mean age of 52 +/- 16 years) with dilated cardiomyopathy. The findings were grouped according to the NYHA classification and compared with a normal cohort of 38 patients (mean age of 42 +/- 10 years). Furthermore, the influence of different cardioactive substances used in the treatment of cardiac failure was analyzed in more detail. Patients in NYHA class II already demonstrated an increased activity of the sympathicoadrenal, renin-angiotensin-aldosterone system (RAAS), vasopressin, and ANF system. The highest values were found in patients of NYHA class IV. In these patients, norepinephrine was enhanced by a factor of 7, epinephrine by a factor of 2, plasma renin activity by a factor of 7, angiotensin II by a factor of 2.5, aldosterone by a factor of 5, vasopressin by a factor of 1.5, and ANF by a factor of 4 compared with those in normal subjects. The highest correlation coefficient was found for norepinephrine (r = 0.84). The acute application of 1-2 mg/kg of body weight of enoximone in patients with dilated cardiomyopathy (n = 15) resulted only in a significant lowering of the atrial natriuretic factor as an indicator for drug-induced unloading effects (venous pooling). All the parameters showed only a tendency; in none could statistical significance be established. Application of 0.75 mg/kg of body weight of enoximone i.v. in patients with coronary artery disease (n = 17) has no direct influence either on the sympathoadrenal, the ANF, or the prostaglandin systems. It could be demonstrated that the mode of medical treatment influences the parameters of vasoconstrictor systems in different ways.

Effects of rhein on renal arachidonic acid metabolism and renal function in patients with congestive heart failure

In a randomized double-blind cross-over study the effects of rhein (administered as diacetyl-rhein 50 mg b.d. for 5 days) and placebo on renal arachidonic acid metabolism and renal function have been compared in 12 elderly patients (mean age 75.2 years) with congestive heart failure, whose renal function was known to be dependent on the integrity of the renal prostaglandin system. Rhein like placebo, did not induce any change in the urinary excretion of prostaglandin (PG) E2, 6-keto-PGF1 alpha and thromboxane (TX) B2, nor did it affect creatinine clearance, blood urea, urine output, natriuresis, body weight, plasma renin activity or plasma aldosterone concentration. Separate analysis of the results obtained in the 5 patients receiving diuretic treatment did not show any significant effect of rhein as compared with placebo on the parameters investigated. Serum TXB2 concentration during whole blood clotting, as an index of platelet arachidonic acid metabolism, also showed no significant difference when DAR and placebo were compared. It is concluded that in patients with congestive heart failure rhein does not inhibit renal or platelet eicosanoid metabolism, nor does it modify renal function, sodium excretion or the renal response to diuretics.

Alterations to the vascular vasodepressor prostaglandin system in DOCA-salt hypertensive rats and their enzymatic analysis.

To define the roles of vascular prostacyclin (PGI2) synthase for PGI2 generation in deoxycorticosterone acetate (DOCA)-salt hypertension, we investigated PGI2 synthase, phospholipase A2 and phospholipase C activities in the aortic wall of DOCA-salt prehypertensive and established hypertensive rats. Vascular PGI2 generation in the DOCA-salt hypertensive rats was increased by 91%, and was associated with an 88% increase in PGI2 synthase activity and lowered phospholipase C and A2 activity. In the prehypertensive stage, DOCA-salt rats showed reduced vascular PGI2 generation. Prostacyclin synthase activity was equal to that of controls. These data clearly suggest that DOCA-salt hypertensive rats increase their vascular PGI2 generation when they develop hypertension, and that this may be due to the activation of vascular PGI2 synthase.

Effects of exercise on parameters of blood coagulation, platelet function and the prostaglandin system.

Acute exercise causes a temporary short lasting activation of blood coagulation, platelet function and the prostaglandin system, the extent of these alterations being significantly less pronounced in well trained athletes than in untrained persons. The reversal is also much faster in athletes, thus providing an underestimated indicator of the individual training status. Changes in platelet function and some plasma parameters of coagulation exhibit a significant correlation to base excess, pH and lactate. Immediately after acute exercise there is, therefore, an increased risk for acute thrombosis if an additional risk such as doping and/or smoking and/or contraceptive pill use is present. This risk is again higher in untrained than in well exercised persons. Patients with clinically manifest atherosclerosis (predominantly with risk factors) performing only occasionally anaerobic exercise are more likely to be at special risk. The overall response of the coagulation system, platelet function and prostaglandin system is significantly impaired. In contrast, regular exercise causes decreased activity of platelets and the coagulation system resulting in an improvement in haemostatic balance. As well as the psychological factors beneficially influencing the subjective feeling, it seems rather likely that the above mentioned mechanisms may be one factor underlying the decreased death rate from cardiovascular disease in persons performing regular physical activity.

Intrarenal thromboxane A2 generation reduces the furosemide-induced sodium and water diuresis in cirrhosis with ascites

To assess the effects of intrarenal thromboxane A2 generation on furosemide-induced sodium and water excretion we administered furosemide (40 mg i.v.) to 8 nonazotemic cirrhotic patients with ascites and 8 healthy subjects before and after the administration of OKY 046 (200 mg twice orally), a powerful thromboxane-synthase inhibitor. Selective thromboxane-synthase inhibition significantly reduced basal and postfurosemide (1 h) urinary thromboxane B2 excretion in healthy subjects (65% before and 62% after furosemide) as well as in cirrhotic patients (52% before and 67% after furosemide) without affecting urinary prostaglandin E2 and 6-keto prostaglandin F1α excretion. During the first hour after furosemide administration, OKY 046 administration significantly enhanced postfurosemide water excretion (milliliters per minute) in both healthy subjects (from 8.5 ± 2.0 to 11.6 ± 2.1, p < 0.001) and cirrhotic patients (from 1.1 ± 0.8 to 4.2 ± 0.5, p < 0.005), whereas furesemide-induced natriuresis (microequivalents per minute) was significantly increased only in the latter group (from 973 ± 125 to 1405 ± 121, p < 0.05). Our data indicate that intrarenal thromboxane A2 generation, elicited by furosemide administration, may reduce the effects of the drug on water and sodium diuresis. Such a reduction seems to be more marked in the presence of an activated intrarenal prostaglandin system, suggesting that renal thromboxane A2 may represent an additional factor in conditioning the impaired responsiveness to furosemide, which is frequently observed in cirrhotic patients with ascites.

24 OXYGEN RADICALS PRODUCE PULMONARY HYPERTENSION IN PIGS

Top of pageAbstract The effect of oxygen radicals on the pulmonary circulation in pigs was studied. A bolus infusion of xanthine oxidase (XO) was given with or without hypoxanthine (Hx) into the right atrium. Pulmonary artery pressure (PAP) and pulmonary flow (PAQ) were measured continuously, and the pulmonary resistance (PR) was calculated. Three groups were studied: 1) Pigs given XO (1 U/kg). 2) Pigs given XO combined with Hx. 3) Pigs pretreated with indomethacin (7.5 mg/kg) before infusion of XO. Results: The table shows absolute differences from baseline values 20 minutes after XO was administered. Infusion of XO both with and without Hx gave a significant increase in PAP and PR with PAQ decreasing concomitantly. Animals pretreated with indomethacin did not show any significant differences from baseline levels. This study demonstrates that XO potently constricts the pulmonary circulation in pigs. Since pretreatment with indomethacin only gives a blunted response, the effect may be mediated by the prostaglandin system.

Interference with the prostaglandin system as a therapeutical concept to protect the myocardium during ischemic stress: experimental studies with inhibition of thromboxane synthesis.

The characterization of thromboxane A2 as vasoconstrictor and potent stimulus of platelet aggregation has led to attempts to overcome these effects obviously unfavourable in ischemia. As an attractive approach, we examined potentially protective results of thromboxane synthetase inhibition on canine myocardium stressed by transient ischemia, using as inhibitor the imidazole derivative UK 38.485. On anaesthetized open-chest mongrel-dogs (n = 5) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the LAD artery. In each experiment 3-4 control occlusions were compared to 3-4 occlusions under therapy. The efficiency of the drug (5 mg/kg body weight, i.v., 30 min before therapy occlusion) was examined (a) by quantification of the energy deficit occurring as the difference between oxygen demand and uptake during occlusion, (b) by the amounts of potassium, inorganic phosphate, and lactate released in the postischemic reperfusion and (c) by changes of the regional myocardial wall function in the central- and peripheral ischemic zone. Compared to control, premedication with UK 38.485 led to a reduced energy deficit (-39.1%; p less than 0.01) combined with a significant decrease in the release of potassium (-15.7%; p less than 0.001), inorganic phosphate (-20.2%; p less than 0.002), and lactate (-20.7%; p less than 0.01). Regional myocardial wall function was improved in the central and peripheral ischemic region as demonstrated by a significantly reduced systolic bulging. The protective effects seem to be mainly due to enhanced flow to ischemic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms underlying pressure-related natriuresis: the role of the renin-angiotensin and prostaglandin systems. State of the art lecture.

It has long been known that increments in renal perfusion pressure can induce an elevation of urine sodium excretion without changing renal blood flow or glomerular filtration rate. The mechanism underlying this pressure-related natriuresis remains undefined, although the interest in its elucidation has been stimulated by the notion that it may constitute the central phenomenon through which the kidney regulates blood volume and, thereby, blood pressure. Recently, the use of novel experimental techniques has disclosed some important clues about changes in renal hemodynamics that, along with changes in renal humoral regulators, allow us to visualize a possible sequence of events responsible for pressure-related natriuresis. According to this hypothesis, the autoregulatory responses responsible for maintaining glomerular filtration rate are elicited in preglomerular vasculature by changes in renal perfusion pressure. These myogenic responses are coupled through Ca2+ entry in juxtaglomerular cells with inversely related changes in the release of renin and, consequently, with the amount of angiotensin II generated in renal interstitium. The release of renin from juxtaglomerular cells is modulated by the synthesis of prostaglandin I2 from the adjacent endothelial cells. Interstitial angiotensin II could influence sodium tubular reabsorption directly by stimulating sodium transport in proximal renal tubules and indirectly by altering medullary blood flow and, thereby, medullary interstitial pressure. In the renal medulla, the effects of interstitial pressure on sodium reabsorption can be amplified by the release of prostaglandin E2 from interstitial cells. A deficient regulation of this relationship could result in a shift of the pressure-natriuresis curve, leading to hypertension.

Control of alveolar surfactant in rats at rest and during prolonged hyperpnoea: pharmacological evidence for two tissue pools of surfactant.

1. Propranolol, atropine and indomethacin (i.p.) affect neither the amount (PLalv), nor the specific activity (PLalvsp.act.) of alveolar surfactant-type phospholipids lavaged from the lungs of unanaesthetized rats, either at rest or made hyperpnoeic for 24 h with 5%CO2/13%O2/82%N2. 2. Whereas salbutamol (280 micrograms kg-1 body weight, i.p.) consistently increased PLalv and PLalvsp.act., pilocarpine (1.5, 3, 10 and 50 mg kg-1, i.p.) and labetalol (1 and 5 mg kg-1, i.p.) had no effect. The dose of pilocarpine reported by others to release surfactant (150 mg kg-1) induced marked salivation, diarrhoea, chromodacryorrhoea and a three-fold increase in tidal volume. 3. In the isolated perfused lung of the rat, salbutamol (1.5 microM) consistently increased PLalvsp.act, whereas pilocarpine (0.1 and 1 microM) had no effect on these variables. 4. In the isolated perfused lung, the maximum amount of surfactant that could be released by salbutamol (0.5 mM) was smaller than that which could be released in response to an increase in tidal volume (peak inflation pressure 28 cmH2O). 5. When the concentration of salbutamol in the isolated perfused lung was adjusted to produce the same increase in PLalv as did a single simulated deep breath, the PLalvsp.act was significantly increased by salbutamol, but not by the simulated deep breath. 6. We conclude, that neither the autonomic nervous system nor the prostaglandin system is essential for the release of surfactant at rest or during hyperpnoea. Furthermore, we suggest that two pools of surfactant, with different release mechanisms, exist in lung tissue.

Bacterial microflora, endogenous endotoxin, and prostaglandins in small bowel obstruction

The objective of this experimental study of small bowel obstruction was to investigate luminal bacterial colonization and assess the most likely mediator substances responsible for the pathophysiologic alterations, those being endogenous endotoxin and prostaglandins. Eighteen pigs with small bowel obstruction and 11 sham-operated control animals given constant infusion therapy were investigated over 7 days. Bacteria determinations were performed at operation and at sacrifice. Endotoxin levels were determined three times and prostaglandin levels, twice daily in portal and central venous blood. In the pigs with small bowel obstruction, greatly increased microflora with a predominance of E. coli bacteria was observed in the obstructed bowel. Endotoxin measurements proved general release into the circulation, with potentially toxic levels in the systemic circulation arising relatively late on the fourth postobstruction day. Beginning on the first postobstruction day, stimulation of the prostaglandin system occurred which was initially limited to the gastrointestinal tract but spread systemically when the obstruction persisted for more than 5 days. Vasoactive eicosanoids were predominantly involved. The control animals showed none of the alterations seen in the animals with small bowel obstruction.

Prevention of Hypertensive Disorders in Pregnancy

For unknown reasons some women fail to exhibit or maintain proper adaptational circulatory responses to the presence of trophoblast, which may lead to circulatory maladaptation disease (“MAD-disease”). Pregnancy-induced hypertension (PIH) and preeclampsia (PE), and also fetal growth retardation, abruptio placentae, and premature labor may represent clinical expressions of MAD-disease. So far, primary prevention of PIH-PE appears to be not possible, except by means of avoiding pregnancy altogether. However, secondary prevention may be feasible by manipulation of the eicosanoid (prostaglandin) system, a disturbance of which has emerged as an important secondary mechanism in the development of PIH-PE. Results of small controlled studies on secondary prevention of PIH-PE and of other expressions of MAD-disease using low-dose aspirin look promising, but application in clinical practice should await the outcome of larger properly designed clinical trials.

Hormonal regulation of renal function during development.

The present review summarizes current and new knowledge concerning the major hormonal systems that directly or indirectly affect renal function during development. The role of the renin-angiotensin-aldosterone system in regulating renal function during fetal and postnatal life is reviewed. A summary of the role of this system during fetal and postnatal stresses is also provided. The physiological role of the renal kallikrein-kinin system in the control of renal blood flow, renin release and sodium excretion during development is examined. Possible influences of the prostaglandin system on regulation of renal function and renin secretion during fetal and postnatal maturation are explored. The effect of vasopressin on the ability of the fetal and postnatal kidney to concentrate urine and regulate body fluid homeostasis is reviewed in detail. The physiologic action of vasotocin on renal sodium and water homeostasis is described. New information regarding the role of the sympathetic system in the regulation of renal hemodynamics and in the control of renal function during development is presented. Finally, recent studies demonstrating the effect of atrial natriuretic factor and corticosteroids on the developing kidney are discussed.

Control of the bronchial tone.

The tone of airway smooth muscle is the functional expression of a dynamic equilibrium between various excitatory and inhibitory mechanisms. On the excitatory side, the vagal reflex mechanism, mainly activated by central airway irritant receptors, is the most important. Bronchial epithelium plays a pivotal role in the regulation of the responsiveness of these receptors. Cholinergic responses of the bronchial muscle are mediated by muscarinic (M2) receptors. On the inhibitory side, the main mechanism is the adrenergic one: beta 2-receptors are mainly stimulated by circulating adrenaline. A dense population of beta 2-receptors has recently been observed in bronchial epithelium. Nonadrenergic-noncholinergic mechanisms--both excitatory and inhibitory--participate in the regulation of bronchial motor tone, but their role in man is still to be defined. Nonsteroidal anti-inflammatory drugs do not modify bronchial motor tone; thus, in this respect, at least in physiological conditions, a modulatory function of the prostaglandin system can be excluded. Probably the same applies to leukotrienes, but for a definite answer, specific antagonists are needed.